Medicaments

ABSTRACT

Use of a compound of general formula (I): ##STR1## wherein: R 1  represents hydrogen, halogen, trifluoromethyl, nitro, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, arylC 1-6  alkoxy, --CO 2  R 4 , --(CH 2 ) n  CN, --(CH 2 ) n  CONR 5  R 6 , --(CH 2 ) n  SO 2  NR 5  R 6 , C 1-6  alkanoylamino (CH 2 ) n , or C 1-6  alkylsulphonylamino (CH 2 ) n  ; 
     R 4  represents hydrogen, C 1-6  alkyl or arylC 1-6  alkyl; 
     R 5  and R 6  each independently represent hydrogen or C 1-6  alkyl, or R 5  and R 6  together with the nitrogen atom to which they are attached form a ring; 
     n represents 0, 1 or 2; and 
     R 2  and R 3  each independently represent hydrogen, C 1-6  alkyl or benzyl or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexahydroazepino ring; 
     or a physiologically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition where a 5-HT 1  -like agonist is indicated, for example migraine. Novel compounds of formula (I), processes for preparing them and pharmaceutical compositions containing them are also described.

This is a continuation of application Ser. No. 08/167,846, filed Dec.23, 1993, now U.S. Pat. No. 5,464,864.

The present invention relates to certain tetrahydrocarbazole derivativesfor use in the treatment of disorders characterised by excessivevasodilatation, in particular the treatment of migraine.

Migraine is a non-lethal disease which has been reported to be sufferedby one in ten individuals. The main symptom is headache; other symptomsinclude vomiting and photophobia. Currently, the most widely usedtreatment for migraine involves administration of ergotamine,dihydroergotamine or methysergide, which are also used prophylactically.These drugs are inter alia agonists of 5HT₁ -like receptors but alsohave other actions; treatment with them is associated with a number ofadverse side effects. In addition, some patients experience a"withdrawal headache" following the cessation of treatment with an ergotproduct, such as ergotamine, causing them to repeat the treatment andresulting in a form of addiction. More recently various tryptaminederivatives have been proposed for potential use in treating migraine.

In view of the foregoing, there is clearly a need for the provision ofeffective and safe medicaments for the treatment of migraine.

U.S. Pat. Nos. 4,257,952, 4,172,834, 4,062,864 and 3,959,309 disclose abroad class of tetrahydrocarbazoles of the formula: ##STR2## wherein N═Bis inter alia --NHR' or --NR'R" where R' and R" are lower alkyl,aryl-lower alkyl or together form a heterocyclic ring; R is inter aliahydrogen; Q₁ is inter alia hydrogen, halogen, lower alkoxy, cyano, --CO₂R₁ or --CONR₂ R₃ (where R₁ may be hydrogen, lower alkyl or --CH₂ Ar andR₂ and R₃ are hydrogen, lower alkyl or together form a heterocyclicring); Q₂ is inter alia hydrogen, aryl-(lower alkoxy), hydroxy,trihalomethyl, nitro or alkanoylamino, and Q₃ and Q₄ may each be interalia hydrogen. These compounds are said to have analgetic, psychotropicand anthistaminic activities.

It has now surprisingly been found that certain tetrahydrocarbazoles areagonists and partial agonists at 5HT₁ -like receptors and are expectedto have utility in the treatment of conditions wherein a 5-HT₁ -likeagonist or partial agonist is indicated, in particular conditionsassociated with cephalic pain such as migraine, cluster headache andheadache associated with vascular disorders. In this specification theterm `5-HT₁ -like agonist` will hereinafter be used to include partialagonists at this receptor.

The present invention therefore provides the use of compounds of generalformula (I): ##STR3## wherein: R¹ represents hydrogen, halogen,trifluoromethyl, nitro, hydroxy, C₁₋₆ -alkyl, C₁₋₆ -alkoxy, arylC₁₋₆-alkoxy, --CO₂ R⁴, --(CH₂)_(n) CN, --(CH₂)_(n) CONR⁵ R⁶, --(CH₂)_(n) SO₂NR⁵ R⁶, C₁₋₆ alkanoylamino (CH₂)_(n), or C₁₋₆ alkylsulphenylamino(CH₂)_(n) ;

R⁴ represents hydrogen, C₁₋₆ alkyl or arylC₁₋₆ alkyl;

R⁵ and R⁶ each independently represent hydrogen or C₁₋₆ alkyl, or R⁵ andR⁶ together with the nitrogen atom to which they are attached form aring;

n represents 0, 1 or 2; and

R² and R³ each independently represent hydrogen, C₁₋₆ alkyl or benzyl ortogether with the nitrogen atom to which they are attached form apyrrolidino, piperidino or hexahydroazepino ring;

and physiologically acceptable salts thereof, in the manufacture of amedicament for the treatment of a condition where a 5-HT₁ -like agonistis indicated, in particular the treatment or prophylaxis of migraine.

The invention also provides a method of treatment of a condition whereina 5-HT₁ -like agonist is indicated, in particular migraine, whichcomprises administering to a subject in need thereof an effective amountof a compound of formula (I) or a physiologically acceptable saltthereof.

Suitably R¹ represents hydrogen, halogen, cyano, hydroxy, C₁₋₆ alkoxy,arylC₁₋₆ alkoxy, --CO₂ R⁴, --(CH₂)_(n) CONR⁵ R⁶ or --(CH₂)_(n) SO₂ NR⁵R⁶ ; and R² and R³ each independently represent hydrogen or C₁₋₆ alkyl.

It will be appreciated that compounds of formula (I) may contain one ormore assymetric centres, and such compounds will exist as opticalisomers (enantiomers). The invention thus includes all such enantiomersand mixtures, including racemic mixtures, thereof.

In the compounds of formula (I) a halogen atom may be a fluorine,chlorine, bromine or iodine atom. An alkyl group or moiety may have astraight or branched chain. Suitable aryl groups include for exampleunsaturated monocyclic or bicyclic rings and partially saturatedbicyclic rings of up to 12 carbon atoms, such as phenyl, naphthyl andtetrahydronaphthyl. When R⁵ and R⁶ together with the nitrogen atom forma ring, this is preferably a 5 to 7-membered saturated heterocyclicring, which may optionally contain a further heteroatom selected fromoxygen, sulphur or nitrogen. Suitable rings thus include pyrrolidino,piperidino, piperazino and morpholino.

In the above compounds R¹ preferably represents halogen (e.g. bromine),CF₃, C₁₋₆ alkoxy (e.g. methoxy), (CH₂)_(n) CN, --(CH₂)_(n) CONR⁵ R⁶,--(CH₂)_(n) SO₂ NR⁵ R⁶ or C₁₋₆ alkanoylamino. Most preferably R¹represents a group --(CH₂)_(n) CONR⁵ R⁶ wherein n represents 0 and R⁵and R⁶ each independently represent hydrogen, methyl, ethyl or propyl.Advantageously, R⁵ and R⁶ independently represent hydrogen or methyl.

When R¹ represents --CO₂ R⁴, then R⁴ preferably represents C₁₋₆ alkyl.

R² and R³ each preferably represent hydrogen, methyl or ethyl. Mostpreferably NR² R³ is --NH₂.

For use according to the present invention the compound of formula (I)is preferably a partial agonist.

Suitable physiologically acceptable salts will be apparent to thoseskilled in the art and include for example acid addition salts such asthose formed with inorganic acids e.g. hydrochloric, sulphuric orphosphoric acids and organic acids e.g. succinic, maleic, acetic orfumaric acid. Other non-physiologically acceptable salts e.g. oxalatesmay be used for example in the isolation of compounds of formula (I),and are included within the scope of this invention. Also includedwithin the scope of the invention are solyates and hydrates of compoundsof formula (I).

It is believed that compounds of formula (I) wherein R² and R³ bothrepresent hydrogen are novel. Thus in a further aspect the presentinvention provides compounds of formula (IA): ##STR4## wherein R¹ is ashereinbefore defined, and salts thereof.

The present invention further provides the following specific compoundswhich are also believed to be novel:

3-Amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride,

(+)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride,

(-)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-bromo-1,2,3,4-tetrahydrocarbazole hydrochloride,

3-amino-6-methyl-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-(N-methyl carboxamido)-1,2,3,4-tetrahydrocarbazolehemioxalate,

3-amino-6-cyanomethyl-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-(N-methylsulphonamidomethyl)-1,2,3,4-tetrahydrocarbazoleoxalate,

3-amino-6-chloro-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-n-butyloxy-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-sulphonamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-nitro-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-(N,N-dimethylcarboxamido)-1,2,3,4-tetrahydrocarbazolehemioxalate,

3-amino-6-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydrocarbazolehydrochloride,

3-amino-6-(pyrrolidin-1--ylcarbonyl)-1,2,3,4-tetrahydrocarbazolehydrochloride,

3-amino-6-(N,N-diethylcarboxamido)-1,2,3,4-tetrahydrocarbazolehydrochloride,

3-Amino-6-(acetamido)-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-methanesulphonamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-amino-6-carboxamidomethyl-1,2,3,4-tetrahydrocarbazole hydrochloride,

3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-ethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-n-propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-i-propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-dimethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate,

3-pyrrolidinyl-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate, and

3-(N-(methyl)ethylamino)-6-carboxamido-1,2,3,4-tetrahydrocarbazoleoxalate,

3-amino-6-(2-carboxamidoethyl)-1,2,3,4-tetrahydrocarbazole oxalate.

In a further aspect the present invention provides a novel compound offormula (I) e.g. a compound of formula (IA) or any of the above-namedcompounds (in free base form or as a physiologically acceptable salt)for use as a therapeutic agent, in particular as a 5-HT₁ -like agonistor partial agonist, for example for the treatment of migraine.

The invention also provides a process for the preparation of novelcompounds of formula (I).

Compounds of formula (I) may be prepared by methods known in the art forthe preparation of tetrahydrocarbazoles, for example:

A) Reaction of a compound of formula (II): ##STR5## (wherein R¹ is ashereinbefore defined) or an acid addition salt thereof with a compoundof formula (III): ##STR6## (wherein R² and R³ are as hereinbeforedefined) or an N-protected derivative thereof; or

B) Reaction of a compound of formula (IV): ##STR7##

(wherein R¹ is as defined for formula (I) and Z is a leaving group) witha compound of formula HNR² R³ ;

C) Reacting a compound of formula (V): ##STR8## with an acylating orsulphonylating agent;

D) Conversion of one compound of formula (I) into another compound offormula (I) e.g.

(i) to prepare a compound of formula (I) wherein R¹ represents--(CH₂)_(n) CONH₂ or CO₂ R⁴, hydrolysis of a compound of formula (I)wherein R¹ represents --(CH₂)_(n) CN, or an N-protected derivativethereof;

(ii) to prepare a compound of formula (i) wherein R¹ represents --CONR⁵R⁶, amination of a compound of formula (I) wherein R¹ represents --CO₂H, or an N-protected derivative thereof; or

(iii) to prepare a compound of formula (I) wherein one of R² and R³ ishydrogen and the other is C₁₋₆ alkyl, alkylation of a compound (I) inwhich R² and R³ are both hydrogen;

(iv) to prepare a compound of formula (I) wherein R¹ represents hydroxy,cleavage of a compound wherein R¹ represents alkoxy or aralkoxy;

followed if necessary by deprotection of any protected nitrogen atomsand if desired by salt formation.

Process (A), which is a form of the Fischer indole synthesis, may becarried out using methods well known in the art. Thus, the reaction maybe effected in a solvent, for example an alcohol such as ethanol orbutanol; or acetic acid, and at a temperature in the range 0° to 150° C.

Hydrazines of formula (II), which are usually employed as thehydrochloride salt, are known compounds, or may be prepared byconventional methods.

A cyclohexanone of formula (III) may be prepared by oxidation of thecorresponding cyclic alcohol, using an oxidising agent such aspyridinium chlorochromate, pyridinium dichromate, dipyridine Cr (VI)oxide, sodium hypochlorite, calcium hypochlorite or manganese dioxide.

The leaving group Z in the compounds of formula (IV) may be for examplea halogen atom, or a sulphonyloxy group e.g. p-toluenesulphonyloxy ormethanesulphonyloxy. Process (B) may be effected in an inert organicsolvent, such as an alcohol e.g. methanol or an ether e.g.tetrahydrofuran and at a temperature in the range 0° to 150° C.Compounds of formula (IV) may be obtained by reacting a hydrazine offormula (II) with an appropriately substituted cyclohexanone compound.When Z is acyloxy or sulphonyloxy this may be prepared from a compound(IV) wherein Z is hydroxy, using standard procedures.

Suitable acylating and sulphonylating agents which may be used inprocess (C) include carboxylic and sulphonic acid chlorides (e.g. acetylchloride or methanesulphonylchloride) alkyl esters, activated esters andsymmetrical and mixed anhydrides. The reaction may be carried out in anorganic solvent such as a haloalkane (e.g. dichloromethane), an amide(e.g. N,N-dimethylformamide; an ether (e.g. tetrahydrofuran) or atertiary amine such as pyridine. In general a base will also be used,e.g. triethylamine, dimethylaminopyridine, or an alkali metal carbonateor bicarbonate. The reaction may be effected at a temperature in therange of -10° to 100° C.

Compounds of formula (V) may be prepared by methods analogous toprocesses (A) and (B) hereinbefore described. Alternatively a compoundof formula (V) may be obtained by subjecting a compound of formula (I)wherein R¹ is nitro to reduction, e.g. by catalytic hydrogenation.

It is well known in the chemical art that hydrolysis of a nitrileinitially results in an amide, which can be further hydrolysed to anacid. It will therefore be appreciated that the precise product ofprocess (Di) will depend upon the reaction conditions chosen for thehydrolysis. To obtain a compound wherein R¹ represents H₂ NCO-- thehydrolysis is preferably effected using hydrogen peroxide in thepresence of an alkali hydroxide e.g. sodium hydroxide, in a solvent suchas an alcohol e.g. methanol. Other suitable means of hydrolysis includeacetic acid and BF₃ ; or formic acid and hydrobromic or hydrochloricacid. To prepare a compound wherein R¹ represents --COOH acid or basecatalysed hydrolysis may be used.

Process (Dii) may be effected by reacting a compound of formula (I)wherein R¹ is --CO₂ H with an amine HNR⁵ R⁶, in the presence of acoupling agent e.g. dicyclohexylcarbodiimide orN,N'-carbonyldiimidazole. Alternatively the carboxylic acid startingmaterial may first be reacted to form an activated derivative of thecarboxyl group, for example an acid chloride, acid anhydride oractivated ester, which is then reacted directly with an amine HNR⁵ R⁶.The carboxylic acid may also be activated in situ for example bytreating with hexamethylphosphoroustriamide.

Alkylation according to process (Diii) may be effected by reacting anamine of formula (I) with an acylating agent, for example an anhydride,such as acetic or propionic anhydride, to form an intermediate in whichone of R² or R³ is --C(O)C₁₋₆ alkyl, followed by reduction of saidintermediate to give the desired product. Other reagents and conditionswill be apparent to those skilled in the art.

Cleavage according to process (Div) may be effected by reduction, usingmethods well known in the art.

It will be appreciated that in many of the above reactions it will benecessary to protect the group --NR² R³ when one or both of the groupsR² and R³ represent hydrogen. Suitable N-protecting groups arewell-known in the art and include for example acyl groups such asacetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl or phthaloyl; and aralkyl groups such as benzyl,diphenylmethyl or triphenylmethyl. When R² and R³ both representhydrogen the nitrogen atom is preferably protected as the phthalimide.The protecting groups should be easily removable at the end of thereaction sequence. N-deprotection may be effected by conventionalmethods, for example a phthaloyl group may be removed by reaction withhydrazine; an acyl group such as benzoyl may be cleaved by hydrolysisand an aralkyl group such as benzyl may be cleaved by hydrogenolysis.

When a compound of formula (I) is obtained as a mixture of enantiomersthese may be separated by conventional methods, for example by reactionof the mixture with a suitable optically active acid such as d-tartaricacid, 1-malic acid, 1-mandelic acid, 1-gulonic acid or2,3:4,6-di-O-isopropylidene-keto-L-gulonic acid to give twodiastereoisomeric salts which may be separated e.g. by crystallisation.

Alternatively mixtures of enantiomers may be separated bychromatography, for example on a chiral HPLC column.

Compounds of formula (I) have been found to be agonists and partialagonists at 5HT₁ -like receptors and are expected to have utility in thetreatment and/or prophylaxis of migraine, and other conditionsassociated with cephalic pain.

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect pharmaceuticalcompositions comprising a novel compound of formula (I) or aphysiologically acceptable salt thereof and a physiologically acceptablecarrier.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral, buccal, sublingual, nasal,rectal or transdermal administration and the pharmaceutical compositionsadapted accordingly.

The compounds of formula (I) and their physiologically acceptable saltswhich are active when given orally can be formulated as liquids, forexample syrups, suspensions or emulsions, tablets, capsules andlozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or physiologically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or physiologically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochlorohydrocarbon. The aerosol dosageforms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to250 mg (and for parenteral administration contains preferably from 0.1to 25 mg) of a compound of the formula (I) or a physiologicallyacceptable salt thereof calculated as the free base.

The physiologically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, preferably between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a physiologically acceptable salt thereofcalculated as the free base, the compound being administered 1 to 4times per day. Suitably the compounds will be administered for a periodof continuous therapy, for example for a week or more.

BIOLOGICAL DATA 5-HT₁ -like Receptor Screen

Dog Saphenous Vein

Helicoids of dog saphenous vein were set up at 37° C. in modified Krebssolution at a resting force of 10 mN. The solution also contained 1μmol/l each of ketanserin prazosin, atropine and mepyramine, 6 μmol/lcocaine and 200 μmol/l ascorbate. Nearly isomeric contractions weremeasured with force transducers on a polygraph. The tissues were exposedtwice to 5-hydroxytryptamine (5-HT) 2 μmol/l followed by washes. Acumulative concentration-effect curve was determined, followed by acurve to 5-HT in the presence of the highest used concentration of testcompound. Contractions caused by the test compound were compared withthose caused by 5-HT. The intrinsic activity of the test compound wascalculated as the ratio of the maximum test compound-induced effect overthe effect caused by 2 μmol/l 5-HT. The EC₅₀ of the test compound wasestimated from the corresponding effect curve. When appropriateequilibrium dissociation constants Kp were estimated by the method ofMarano & Kaumann (1976, J. Pharmacol. Exp. Ther. 193%, 518-525).

In this screen the compounds of Examples 2, 4, 5, 6, 9, 10, 11, 13, 17,18, 21 and 24 had EC₅₀ 's in the range 0.1 to 15 μmol.

RABBIT BASILAR ARTERY Methods

Experiments were performed in intracranial arteries from rabbit isolatedbasilar artery in a similar method to one described previously (Parsonsand Whalley, 1989. Eur J Pharmacol 174, 189-196.).

In brief, rabbits were killed by overdose with anaesthetic (sodiumpentobarbitone). The whole brain was quickly removed and immersed in icecold modified Kreb's solution and the basilar artery removed with theaid of a dissecting microscope. The Krebs solution was of the followingcomposition (mM) Na⁺ (120); K⁺ (5); Ca²⁺ (2.25); Mg²⁺ (0.5); Cl⁻ (98.5);SO₄ ²⁻ (1); EDTA (0.04), equilibrated with 95% O₂ /5% CO₂. Theendothelium was removed by a gentle rubbing of the lumen with a finemetal wire. Arteries were then cut into ring segments (ca 4-5 mm wide)and set up for recording of isometric tension in 50 ml tissue baths inmodified Krebs solution with the additional supplement of (mM); Na²⁺(20); fumarate (10); pyruvate (5); L-glutamate (5) and glucose (10). Thearteries were then placed under a resting force of 3-4 mN maintained at37° C. and the solution bubbled with 95% O₂ /5% CO₂.

After tests for initial reactivity with 90 mM KCl depolarising solutionand for lack of acetylcholine-induced relaxation of 5-HT (10 mM)precontraction, cumulative concentration-effect curves (2 nM-60 mM) to5-HT were constructed in the presence of ascotbate 200 mM, cocaine 6 mM,indomethacin 2.8 mM, ketanserin 1 mM and prazosin 1 mM.

Following a 45-60 min wash period, cumulative concentration-effectcurves to the test compounds or 5-HT (as a time match control) wereconstructed in the presence of ascorbate, indomethacin, cocaine,ketanserin and prazosin.

In this screen the compounds of Example 2, 5, 6, 15, 17, 24, 25, 26, 28and 29 had EC₅₀ 's in the range 0.04 to 15.

EXAMPLE 1

3-Amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride

A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) inwater (60 ml) was brought to pH 8 with aqueous sodium bicarbonatesolution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was addedfollowed by tetrahydrofuran (until homogenous solution was obtained).The clear solution was stirred at room temperature overnight. Duringthis time a white solid was precipitated. The tetrahydrofuran wasremoved in vacuo and the remaining aqueous solution was extracted withethyl acetate until the solution was clear. The ethyl acetate extractswere combined, washed with water, dried (MgSO₄) and concentrated to give4-phthalimido cyclohexanol as a white solid (7.1 g).

A solution of 4-phthalimido cyclohexanol (7.1 g, 0.029 mole) indichloromethane (250 ml) was treated with pyridinium chlorochromate (8.6g, 0.04 mole) and the resulting dark mixture was stirred at roomtemperature overnight. Diethyl ether (50 ml) was added and the mixturefiltered through keiselguhr. The filtrate was concentrated in vacuo andthe residue purified by column chromatography (SiO₂ ; CHCl₃ /EtOAc) togive 4-phthalimido cyclohexanone as a white solid (6.4 g).

4-Cyanophenyl hydrazine hydrochloride (4.41 g, 0.026 mole) was dissolvedin acetic acid (100 ml) and sodium acetate (2 g) was added.4-Phthalimido cyclohexanone (6.4 g, 0.026 mole) was added and themixture heated under reflux overnight. The solvent was removed in vacuoand the residue triturated with methanol to give3-phthalimido-6-cyano-1,2,3,4-tetrahydrocarbazole as a beige solid, (5.3g).

A suspension of the above product (1 g) in ethanol (40 ml) was treatedwith hydrazine in water (10 ml). The reaction mixture was stirred atroom temperature overnight during which time the reactants dissolved.The solvent was removed in vacuo and the residue partitioned betweenaqueous potassium carbonate and ethyl acetate. The ethyl acetatesolution was washed with water, dried and concentrated in vacuo to give3-amino-6-cyano-1,2,3,4-tetrahydrocarbazole as a beige solid (500 mg).This product was converted into the hydrochloride salt to give the titlecompound, mp 289° C. (dec.).

¹ H NMR [250 MHz, CD₃ OD] δ 1.98-2.18 (1H, m), 2.25-2.40 (1H, m), 2.77(1H, dd), 2.98 (2H, m), 3.22 (1H, dd), 3.68 (1H, m), 7.34 (1H, d), 7.43(1H, d), 7.82 (1H, s).

EXAMPLE 2

3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride

The product of Example 1 (400 mg) was dissolved in tetrahydrofuran, anddi-t-butyl dicarbonate (500 mg) was added. The mixture was stirred atroom temperature overnight. The solvent was removed in vacuo and theresidue purified by column chromatography (SiO₂ ; CHCl₃ /EtOAc) to give3-t-butyloxycarbonylamino-6-cyano-1,2,3,4-tetrahydrocarbazole (40 mg).

A mixture of the above product nitrile (440 mg), aqueous hydrogenperoxide (30%, 0.5 ml) and sodium hydroxide (aq) (20%, 0.5 ml) inmethanol (25 ml) was stirred at room temperature overnight. Sodiummetabisulphite (100 mg) was added and the solvent removed in vacuo. Theresidue was dissolved in ethyl acetate and the ethyl acetate layer wasseparated, dried and concentrated in vacuo to give a gummy solid whichwas purified by column chromatography (SiO₂ ; CHCl₃ /EtOAc) to give3-t-butyloxycarbonylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole as awhite solid (400 mg), mp 270° C. (dec).

The above product (400 mg, 0.0012 mole) was dissolved in dioxan (100 ml)and HCl gas was bubbled through the solution for 20 minutes. During thistime a white solid was precipitated. Excess hydrogen chloride was sweptfrom the solution by bubbling through N₂, and the solid product,3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride wascollected by filtration, washed with diethyl ether and dried to give thetitle compound as a white solid (300 mg). m.p. 270 (dec).

¹ H NMR [250 MHz, DMSO-d⁶ ] δ 1.96 (1H, m), 2.16-2.30 (1H, m), 2.74 (1H,dd), 2.85 (2H, m), 3.12 (1H, dd), 1 signal obscured by H₂ O at ca. 3.6,7.08 (1H, brd.s), 7.27 (1H, d), 7.61 (1H, d), 7.87 (1H, brd.s), 7.99(1H, s), 8.39 (3H, brd.s).

EXAMPLE 3

3-Amino-6-methoxy-1,2,3,4-tetrahydrocarbazole hydrochloride

Reaction of 4-methoxyphenyl hydrazine hydrochloride (0.87 g, 5.0 mmol)with 4-phthalimido-cyclohexanone (1.22 g, 5.0 mmol) in ethanol (20 ml)heated under reflux for 2 hr, followed by cooling and removal of theprecipitated solid by filtration gave3-phthalimido-6-methoxy-1,2,3,4-tetrahydrocarbazole (1.62 g).

The above product (1.57 g, 4.5 mmol) was suspended in ethanol (100 ml)and treated with hydrazine hydrate (23 ml) while stirring at roomtemperature. After 30 min, the solvent was removed in vacuo and theresidue was partitioned between K₂ CO₃ (aq) and EtOAc. The latter layerwas separated, washed with water, dried (MgSO₄) and evaporated todryness. This residue was dissolved in ethanol and treated with etherealHCl until cloudy, then left to stand overnight to yield the titlecompound (0.95 g) mp>250° C. ¹ H NMR [250 MHz, DMSO-d⁶ ] δ 1.81-2.02(1H, m), 2.10-2.28 (1H, m), 2.65 (1H, dd), 2.82 (2H, m), 3.02 (1H, dd),1 signal obscured by H₂ O at ca. 3.5, 3.74 (3H, s), 6.66 (1H, d), 6.84(1H, d), 7.14 (1H, d), 8.16 (3H, brd.s).

EXAMPLE 4

3-Amino-6-bromo-1,2,3,4-tetrahydrocarbazole hydrochloride

Reaction of 4-bromophenylhydrazine hydrochloride (4.0 g, 18.1 mmol) with4-phthalimido-cyclohexanone (4.39 g, 18.1 mmol) in refluxing n-butanolfor 20 min, followed by cooling, filtration, and evaporation of thefiltrate to dryness yielded3-phthalimido-6-bromo-1,2,3,4-tetrahydrocarbazole as an orange solid(7.45 g).

This product (0.33 g, 0.83 mmol) was suspended in ethanol (13 ml) andtreated with hydrazine hydrate (3 ml), then left to stir at roomtemperature overnight. The solid precipitate was filtered off, and thefiltrate was evaporated to dryness and partitioned between K₂ CO₃ (aq)and ethylacetate. After separation of the organic layer, washing withwater, drying (MgSO₄) and evaporation to dryness, the residue wasdissolved in MeOH and treated with HCl gas. Solvent was removed in vacuoand the residue was crystallized from ethanol/ethyl acetate to yield thetitle compound as a cream-coloured solid (0.15 g), mp 308°-310° C. ¹ HNMR [250 MHz, DMSO-d⁶ ] δ 1.91 (1H, m), 2.10-2.26 (1H, m) 2.63 (1H, dd),2.84 (2H, m), 3.04 (1H, dd), 3.50 (1H, m), 7.12 (1H, d), 7.24 (1H, d),7.55 (1H, s), 8.15 (2H, brd.s), 11.12 (1H, s).

EXAMPLE 5

3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole

4-Carboxamidophenylhydrazine hydrochloride (2.87 g) and4-phthalimidocyclohexanone (3.00 g) were mixed in acetic acid and themixture was heated under reflux for 2 hr. After cooling, the mixture wasneutralized using aq. potassium carbonate solution, and the yellow solidthus obtained was filtered, washed with water, and dried. Purificationby column chromatography (SiO₂ ; CHCl₃ /CH₃ OH) gave3-phthalimido-6-carboxamido-1,2,3,4-tetrahydrocarbazole (2.8 g).

The above product (1.0 g) was suspended in ethanol (10 ml) and hydrazinehydrate (5 ml) was added. A clear solution was obtained, and the mixturewas left to stir overnight, to yield a precipitate. The whole mixturewas evaporated to dryness, washed with aq. K₂ CO₃ solution, and water,to leave the title compound3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole (0.44 g), as themonohydrate, mp. 146°-148° C.

¹ H NMR [250 MHz, DMSO-d6] δ 1.49-1.77 (1H,m), 1.83-2.03 (1H,m),2.17-2.40 (1H,m), 2.62-2.80 (2H,m), 2.90 (1H, dd), 1 signal obscured byH₂ O at ca. 3.1, 7.03 (1H, brd.s), 7.18 (1H,d), 7.58 (1H, d), 7.83(1H,brd.s), 7.98 (1H, s).

EXAMPLE 6

(+)- and (-)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazolehydrochloride

Method 1

(+)-3-t-Butyloxycarbonylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazolewas separated into its enantiomers using chiral HPLC: (chiralcel OD 4.6mm column, eluting with hexane/ethanol 85:15). The (+)-enantiomer wascollected first and had mp=150°-152° C. and [α]_(D) ²⁵ =+70.1 (inmethanol, 0.41% w/v). The (-)-enantiomer had mp=150°-152° C. and [α]_(D)²⁵ =-79.4 (in methanol, 0.40% w/v). The (+)-enantiomer was converted tothe parent amine hydrochloride by treating with HCl gas in dioxane, tofurnish the (+)-enantiomer of3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride,mp=248°-251° C., [α]_(D) ²⁵ =+26.2 (in methanol, 0.50% w/v). The(-)-enantiomer of3-t-butyloxycarbonylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole wassimilarly converted into the (-)-enantiomer of3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride,mp=248°-251° C., [α]_(D) ²⁵ =-28.6 (in methanol, 0.50% w/v).

Method 2

(±)-6-carboxamido-3-amino-1,2,3,4-tetrahydrocarbazole was treated withone equivalent of 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid inmethanol to give the salt of the (+)-enantiomer, in 38% yield (withrespect to racemate) and 84% enantiomeric excess (ee). This material wasrecrystallized twice from methanol to give the salt of the(+)-enantiomer in 25% overall yield (with respect to racemate), and >98%ee. This product was converted to the hydrochloride salt first bytreatment with aqueous alkali, and the precipitated free base treatedwith 2M aq. HCl in ethanol, to give(+)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride.

EXAMPLE 7

3-Amino-6-methyl-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (2.16 g) with 4-tolylhydrazinehydrochloride (1.41 g), and subsequent deprotection of the product bythe method described in example 3, gave the title compound free base,which was converted to the oxalate salt (0.23 g), mp 272°-5° C.

EXAMPLE 8

3-Amino-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (0.37 g) with4-ethoxycarbonylphenylhydrazine hydrochloride (0.33 g), and subsequentdeprotection by the method described in example 3, gave the titlecompound free base. This was converted to the oxalate salt (0.11 g), mp230°-240° C. dec.

EXAMPLE 9

3-Amino-6-(N-methyl carboxamido)-1,2,3,4-tetrahydrocarbazole hemioxalate

Reaction of 4-phthalimidocyclohexanone (1.20 g) with4-(N-methylcarboxamido)-phenylhydrazine hydrochloride (1.00 g), andsubsequent deprotection by the method described in example 3, gave thetitle compound free base. This was converted to the hemioxalate salt(0.22 g), mp 227° C. dec.

EXAMPLE 10

3-Amino-6-cyanomethyl-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (1.05 g) with4-cyanomethylphenylhydrazine hydrochloride (0.79 g), and subsequentdeprotection by the method described in example 3, gave the titlecompound free base, which was treated with oxalic acid to give theoxalate salt (0.49 g), mp 219°-224° C. dec.

EXAMPLE 11

3-Amino-6-(N-methylsulphonamidomethyl)-1,2,3,4-tetrahydrocarbazoleoxalate

Reaction of 4-phthalimidocyclohexanone (0.42 g) with4-(N-methylsulphonamidomethyl) phenyl hydrazine hydrochloride (0.44 g),and subsequent deprotection by the method described in example 3, gavethe title compound free base. This was treated with oxalic acid to givethe oxalate salt (0.15 g), mp 218°-222° C. dec.

EXAMPLE 12

3-Amino-6-chloro-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (6.7 g) with 4-chlorophenylhydrazine hydrochloride (4.93 g), and subsequent deprotection by themethod described in example 3, gave the title compound free base, whichwas treated with oxalic acid to give the oxalate salt (2.77 g),dec >220° C.

EXAMPLE 13

3-Amino-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (1.14 g) with 4-trifluoromethylphenyl hydrazine hydrochloride (1.00 g), and subsequent deprotection bythe method described in example 3, gave the title compound free base(0.40 g). This was treated with oxalic acid to give the oxalate salt, mp212°-213° C.

EXAMPLE 14

3-Amino-6-n-butyloxy-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (1.12 g) with 4-n-butyloxyphenylhydrazine hydrochloride (1.00 g) and subsequent deprotection by themethod described in example 3, gave the title compound free base. Thiswas treated with oxalic acid to give the oxalate salt (0.47 g), mp227°-229° C.

EXAMPLE 15

3-Amino-6-sulphonamido-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (1.00 g) with 4-sulphonamidophenyl hydrazine hydrochloride (1.08 g), and subsequent deprotection bythe method described in example 3, gave the title compound free base.This was converted to the oxalate salt (0.090 g), dec >200° C.

EXAMPLE 16

3-Amino-6-Nitro-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimidocyclohexanone (1.28 g) with 4-nitrophenylhydrazine hydrochloride (1.00 g), and subsequent deprotection by themethod described in example 3, gave the title compound free base, whichwas converted to the oxalate salt (0.25 g), mp 275°-277° C.

EXAMPLE 17

3-Amino-6-(N,N-dimethyl carboxamido)-1,2,3,4-tetrahydrocarbazolehemioxalate

3-Amino-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole (260 mg, 1.0 mmol)was suspended in dry THF (5 ml), and di-tert butyl dicarbonate (320 mg,1.5 mmol) was added. A clear solution was obtained after 10 min. Themixture was left to stir for 20 hr, then the solvent was removed, andthe residue was dissolved in ethyl acetate, washed with aqueous sodiumbicarbonate solution, and dried (MgSO₄). After removal of ethyl acetate,the residue was triturated with ether and hexane to give3-t-butyloxycarbonylamino-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole(310 mg).

The above product (556 mg, 1.55 mmol) was suspended in ethanol (5 ml)and 2M NaOH (3 ml) was added. The mixture was heated under reflux for 1hr and evaporated to dryness. The residue was dissolved in water andneutralized with acetic acid, when3-t-butyloxycarbonylamino-6-carboxy-1,2,3,4-tetrahydrocarbazoleprecipitated out as a white solid (425 mg). A solution of the aboveproduct (400 mg, 1.2 mmol) in dry DMF (8 ml) was treated with hexamethylphosphorous triamide (198 mg, 1.2 mmol), and cooled to -10° C.Dimethylamine gas was bubbled into the mixture for 10 min at thistemperature, then carbon tetrachloride (185 mg, 1.2 mmol) was addeddropwise, under an atmosphere of nitrogen. The mixture was left to stirat room temperature for 1 hr, then the DMF was removed in vacuo. Theresidue was partitioned between ethyl acetate and water, and the organiclayer was washed with saturated aqueous sodium bicarbonate solution,then brine, and dried (Mg SO₄). The solvent was removed in vacuo, andthe residual oil was triturated with ether and hexane and the solidrecrystallized from toluene to give3-t-butyloxycarbonylamino-6-(N,N-dimethylcarboxamido)-1,2,3,4-tetrahydrocarbazole (198 mg).

This product (180 mg, 0.53 mmol) was dissolved in dioxane (5 ml) and HClgas was bubbled through, to precipitate an oil. The solvent was removedin vacuo, and the oil was dissolved in water, and treated with K₂ CO₃solution to bring the pH to 12. The amine free base was then extractedwith ethyl acetate, dried (MgSO₄) and evaporated to dryness. Theresulting oil was dissolved in methanol and treated with oxalic acid toprovide the title compound as a pale pink solid (140 mg) mp=190°-195° C.

EXAMPLE 18

3-Amino-6-(piperidin-1-yl carbonyl)-1,2,3,4-tetrahydrocarbazolehydrochloride

Reaction of3-t-butyloxycarbonylamino-6-carboxy-1,2,3,4-tetrahydrocarbazole (175 mg)with piperidine and the product subsequently deprotected by the methoddescribed for Example 17, gave the title compound, mp=246°-249° C. (55mg).

EXAMPLE 19

3-Amino-6-(pyrrolidin-1-yl carbonyl)-1,2,3,4-tetrahydrocarbazolehydrochloride

Reaction of3-t-butyloxycarbonylamino-6-carboxy-1,2,3,4-tetrahydrocarbazole (140 mg)with pyrrolidine, and the product subsequently deprotected as describedfor Example 17, gave the title compound, mp=201°-212° C. (81 mg).

EXAMPLE 20

3-Amino-6-(N,N-diethyl carboxamido)-1,2,3,4-tetrahydrocarbazolehydrochloride

Reaction of3-t-butyloxycarbonylamino-6-carboxy-1,2,3,4-tetrahydrocarbazole (105 mg)with diethylamine, and deprotection of the product, as described forExample 17, gave the title compound, mp 200°-205° C. (50 mg).

EXAMPLE 21

3-Amino-6-(acetamido)-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of 4-phthalimido cyclohexanone (1.2 g) with4-(acetamido)-phenyl hydrazine hydrochloride (1.0 g), and subsequentdeprotection of the product by the method described in example 3, gavethe title compound free base (570 mg). A portion of this product (50 mg)was treated with oxalic acid in methanol to give the oxalate salt, whichsoftens >170° C. (38 mg).

EXAMPLE 22

3-Amino-6-methanesulphonamido-1,2,3,4-tetrahydrocarbazole oxalate

3-phthalimido-6-nitro-1,2,3,4-tetrahydrocarbazole (4.00 g) was dissolvedin hot ethyl acetate (130 ml). To the cooled solution was added raneynickel, and the mixture was hydrogenated at an initial pressure of 39psi at room temperature for 4 hr. After filtering off the insolublematerials, the filtrate was evaporated to dryness, and extracted twiceinto 20% aqueous methanol and the extracts combined and reduced involume to give 3-phthalimido-6-amino-1,2,3,4-tetrahydrocarbazole (0.31g).

The above product (0.50 g) was dissolved in freshly distilled pyridine(30 ml), and methanesulphonyl chloride (0.28 g) and4-dimethylaminopyridine(46 mg) were added. The mixture was heated withstirring at 50° C. for 5 hr, and then evaporated to dryness. The residuewas dissolved in chloroform, washed with water, brine and aqueous sodiumbicarbonate, then dried (MgSO₄), and evaporated to dryness to give apale yellow solid, which was recrystallized from aqueous ethanol to give3-phthalimido-6-methanesulphonamido-1,2,3,4-tetrahydrocarbazole (0.27g).

The above compound was suspended in ethanol (15 ml) and hydrazinehydrate (2.72 g) was added. After stirring for 25 min at roomtemperature, the mixture was evaporated to dryness, partitioned betweenwater and ethyl acetate, and the aqueous layer re-extracted with ethylacetate. The organic extracts were combined, washed with water, dried(MgSO₄) and evaporated to give a pale yellow solid. This was dissolvedin methanol and treated with oxalic acid (89 mg). Addition of etherresulted in crystallization of the title compound (50 mg), mp 230°-233°C.

EXAMPLE 23

3-Amino-6-carboxamidomethyl-1,2,3,4-tetrahydrocarbazole hydrochloride

3-Amino-6-cyanomethyl-1,2,3,4-tetrahydrocarbazole (2.5 g) and di-t-butyldicarbonate (3.63 g) were stirred in THF (56 ml) for 2 hr. The THF wasevaporated, and the residue was partitioned between aqueous sodiumbicarbonate solution and ethyl acetate. The aqueous phase wasre-extracted with ethyl acetate, and the combined organic extracts werewashed with water, dried (MgSO₄), and evaporated to dryness to leave asolid which was triturated with ether/hexane (20%) to give3-t-butyloxycarbonylamino-6-cyanomethyl-1,2,3,4-tetrahydrocarbazole asan off-white solid (3.44 g).

The above product (7.0 g) was dissolved in DMSO (70 ml), and hydrogenperoxide (100 volume, 3.5 ml) was added. After stirring for an hour,further peroxide (8.5 ml) was added, and the mixture was stirred for 2hr at room temperature. Potassium carbonate (0.84 g) was added, and themixture was stirred overnight and for a further 20 hr. The reactionmixture was poured into water (500 ml) and the resulting white solid wasfiltered off, and recrystallized from methanol to give3-t-butyloxycarbonylamino-6-carboxamidomethyl-1,2,3,4-tetrahydrocarbazole(5.42 g).

The above product (500 mg) was dissolved in dry dioxane (30 ml), and HClgas was bubbled through for 20 min. The resulting solution and depositedgum were evaporated to dryness, and treated with aqueous potassiumcarbonate solution. This was extracted with ethyl acetate, and theextracts were combined, dried (MgSO₄) and evaporated to dryness. Theresidue was dissolved in methanol and treated with excess oxalic acid.Addition of ether led to crystallization of the title compound (250 mg),mp 257°-260° C.

EXAMPLE 24

3-Methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride

4-Cyanophenyl hydrazine hydrochloride (20.2 g) and4-benzoyloxycyclohexanone (25.9 g) were dissolved in glacial acetic acid(400 ml) and the mixture was heated under reflux for 1.5 hr. Afterallowing to cool, the mixture was filtered, and the filtrate wasevaporated to dryness, and neutralized with aqueous sodium bicarbonatesolution to give a solid precipitate, which was purified bychromatography (SiO₂ ; hexane/ethyl acetate) to give3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (18 g). This product(11.6 g) was suspended in ethanol (230 ml) and treated with 2.5% aqueouspotassium hydroxide solution (120 ml), and heated under reflux for 1 hr.The cooled mixture was neutralized with glacial acetic acid andevaporated to a solid residue, which was washed with water, and dried togive 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazole (6.6 g).

The above product (3.57 g) was dissolved in dry pyridine (35 ml) andtreated with tosyl chloride (3.51 g) in dry pyridine (35 ml), and themixture was stirred at 100° C. for 2 hr. After cooling, the solution waspoured into water (500 ml), extracted with ethyl acetate, and the latterextract was washed with 2M HCl, dried (MgSO₄) and evaporated to dryness.Purification by chromatography (SiO₂ ; hexane/ethyl acetate) gave3-tosyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (0.53 g).

This product (0.40 g) was dissolved in 33% methylamine in alcohol (25ml) and heated at 100° C. in a sealed steel vessel for 1.5 hr. Aftercooling, the mixture was evaporated to dryness and purified bychromatography (SiO₂ ; chloroform/methanol) to give3-methylamino-6-cyano-1,2,3,4-tetrahydrocarbazole (0.13 g).

The above product (0.12 g) was dissolved in THF (10 ml) and reacted withdi-tert-butyl dicarbonate (0.36 g) in THF (3 ml) at room temperatureovernight. The reaction mixture was evaporated to dryness, partitionedbetween 2M sodium bicarbonate solution and ethyl acetate, and theorganic extract dried and evaporated to give a white solid. This wastriturated with ether/hexane to give 3-t-butyloxycarbonylmethylamino-6-cyano-1,2,3,4-tetrahydrocarbazole (0.14 g).

This product (0.14 g) was dissolved in methanol (15 ml) and treated witha mixture of 20% aqueous sodium hydroxide 0.20 ml) and 30% hydrogenperoxide (0.20 ml), and the whole mixture was stirred at roomtemperature overnight. Sodium metabisulphite (38 mg) was added, and thesolution was evaporated to dryness, and chromatographed (SiO₂ ;chloroform/10% NH₄ OH in methanol) to give3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole (0.12 g). Theabove compound (0.11 g) was dissolved in methanol (10 ml), and treatedwith 3M hydrochloric acid at room temperature. The mixture wasevaporated to dryness, azeotroping with ethanol to give a solid, whichwas recrystallized from methanol/ether to give the title compound, mp327°-328° C. (80 mg).

¹ H NMR [250 MH_(z), MeOH-d⁴ ] d 1.98-2.20 (1H, m), 2.29-2.49 (1H, m),2.75-2.90 (5H, s+m), 2.90-3.09 (2H, m), 3.52-3.69 (1H, m), 7.31 (1H, d),7.63 (1H, d), 8.05 (1H, s).

EXAMPLE 25

3-Ethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate

1,4-Cyclohexanedione mono-2',2'-dimethyl trimethylene ketal (2.00 g) wasmixed with anhydrous ethylamine (10.0 g) and benzene (10 ml), and themixture was cooled to 5° C. A solution of titanium tetrachloride (0.95g) in benzene (10 ml) was added, dropwise, then the mixture was stirredat room temperature for 1 hr. The mixture was filtered, and evaporatedto dryness to give an oil, which was dissolved in ethanol (30 ml). Tothis solution was added palladium-on-carbon catalyst (100 mg), and themixture was hydrogenated at 50 psi pressure overnight. The catalyst wasfiltered off and the ethanol evaporated to leave4-ethylamino-cyclohexanone 2',2'-dimethyl trimethylene ketal as an oil(2.0 g).

This compound (0.80 g) was dissolved in formic acid (20 ml) and thesolution was heated to 90° C. for 1 hr. Formic acid was evaporated, andthe residue was partitioned between chloroform and 1M hydrochloric acid.The aqueous layer was evaporated to dryness to give4-ethylaminocyclohexanone (0.40 g).

A mixture of the above product (0.40 g) and 4-carboxamidophenylhydrazine hydrochloride (0.60 g) in glacial acetic acid (20 ml) washeated under reflux for 1 hr. The acid was evaporated in vacuo to anoil, which was purified by chromatography (SiO₂ ; CHCl₃ /10% NH₃ inMeOH) to give an oil (0.50 g). Part of this product (150 mg) wasdissolved in methanol and treated with oxalic acid. The solution wastreated with ether to give the title compound as a crystalline solid, mp165°-170° C. (100 mg).

¹ H NMR [250 MHz, DMSO-d⁶ ] d 1.25 (3H, t), 1.81-2.05 (1H, m), 2.20-2.38(1H, m), 2.61-2.79 (1H, m), 2.79-2.94 (2H, m), 2.98-3.28 (3H, dd+s),3.41-3.60 (1H, m), 7.08 (1H, brd. s), 7.28 (1H, d), 7.60 (1H, d), 7.82(1H, brd. s), 8.00 (1H, s), 11.12 (1H, s).

EXAMPLE 26

3-n-Propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate

Propylamine (1.81 g) was dissolved in methanol (12.5 ml), and 1.5M HClin methanol (6.6 ml) was added with cooling. After 1 min,1,4-cyclohexanedione mono-2',2'-dimethyl trimethylene ketal (1.0 g) wasadded, followed after a further 10 min by sodium cyanoborohydride (0.23g). The mixture was stirred at room temperature for 3 days. Theresulting mixture was filtered, and the filtrate was evaporated andtreated with 1M HCl (10 ml) with cooling. The residue was digested toform a solution, which was washed with ether, basified to pH 12 withaqueous sodium hydroxide, and extracted with dichloromethane. Thisextract was washed with saturated aqueous sodium bicarbonate solution,dried (MgSO₄), and evaporated to dryness. Chromatography (SiO₂ ;chloroform/methanol/ammonia) gave 4-n-propylamino cyclohexanone2',2'-dimethyl trimethylene ketal (0.72 g).

This product (0.66 g) was hydrolyzed to the ketone, which was reactedwith 4-carboxamidophenyl hydrazine hydrochloride and converted to theoxalate salt as described for Example 25, to give the title compound(0.44 g), mp >168° C. dec.

EXAMPLE 27

3-i-Propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of isopropylamine (9.54 g) with 1,4-cyclohexanedionemono-2',2'-dimethyl trimethylene ketal (2.0 g) by the method describedfor Example 25 gave 4-i-propylamino cyclohexanone 2',2'-dimethyltrimethylene ketal (2.38 g). This product (0.66 g) was hydrolyzed andreacted with 4-carboxamidophenyl hydrazine hydrochloride (0.45 g), andthe mixture worked up as described above to give the title compound freebase (0.34 g). This was converted to the oxalate, mp >235° C. dec.

EXAMPLE 28

3-Dimethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate

Dimethylamine (10.0 g) was reacted with 1,4-cyclohexanedionemono-2',2'-dimethyl trimethylene ketal (2.0 g) by the method describedfor Example 25 to give 4-dimethylaminocyclohexanone-2',2'-dimethyltrimethylene ketal (0.72 g). This product (0.72 g) was hydrolyzed andreacted with 4-carboxamidophenyl hydrazine hydrochloride (0.47 g) andthe product converted to the oxalate salt as described above to give thetitle compound (0.20 g), mp 99°-101° C.

¹ H NMR [250 MH_(z), DMSO-d⁶ ] d 1.83-2.05 (1H, m), 2.27-2.40 (1H, m)2.72-3.00 (9H, 2m+s), 3.07-3.22 (1H, dd), 3.50-3.68 (1H, m), 7.05 (1H,brd. s), 7.27 (1H, d), 7.60 (1H, d), 7.81 (1H, brd. s), 8.00 (1H, s),11.11 (1H, s).

EXAMPLE 29

3-Benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of benzylamine (0.59 g) with1,4-cyclohexanedionemono-2',2'-dimethyl trimethylene ketal (1.0 g) andsubsequent reduction of the imine with sodium cyanoborohydride by themethod described for Example 26 gave 4-benzylaminocyclohexanone2',2'-dimethyl trimethylene ketal (0.54 g). This product (0.52 g) wasreacted with 4-carboxamidophenyl hydrazine hydrochloride (0.34 g) andthe product treated with oxalic acid to give the title compound, mp>190°C. dec (0.11 g).

EXAMPLE 30

3-Pyrrolidinyl-6-carboxamido-1,2,3,4-tetrahydrocarbazole oxalate

Reaction of pyrrolidine (15.6 g) with 1,4-cyclohexanedionemono-2',2'-dimethyl trimethylene ketal (2.0 g) by the method describedfor Example 25 gave 4-pyrrolidinyl-cyclohexanone-2',2'-dimethyltrimethylene ketal (1.74 g). This product (1.70 g) was hydrolyzed andreacted with 4-carboxamidophenyl hydrazine hydrochloride (1.70 g) andthe product treated with oxalic acid as described above to give thetitle compound (32 mg), mp>190° C. dec.

EXAMPLE 31

3-(N-methyl ethylamino)-6-carboxamido-1,2,3,4-tetrahydrocarbazoleoxalate

Reaction of N-methyl ethylamine (13.0 g) with 1,4-cyclohexanedionemono-2',2'-dimethyl trimethylene ketal (2.0 g) by the method describedfor Example 25 gave 4-(N-methyl ethylamino)-cyclohexanone-2',2'-dimethyltrimethylene ketal (1.71 g). This product (0.86 g) was hydrolyzed andreacted with 4-carboxamidophenyl hydrazine hydrochloride (0.52 g) andworked up as described above to give the title compound (76 mg), mp>130°C. dec.

EXAMPLE 32

3-Amino-6-(2-carboxamidoethyl)-1,2,3,4-tetrahydrocarbazole oxalate

A mixture of 4-nitrocinnamic acid (22.5 g) and thionyl chloride (20.8 g)in benzene (160 ml) was heated under reflux for 4 h. The resultingorange mixture was filtered and evaporated to give the acid chloride(22.9 g). This was dissolved in dichloromethane (1 l), and ammonia gaswas bubbled through, with cooling to below 20° C. and stirring. Solventwas removed in vacuo, and the residue was dissolved in hot ethyl acetateand the solution was shaken with 1M sodium hydroxide solution. Theresulting organic phase was dried, filtered and evaporated to leave aresidue which was slurried with ethyl acetate to give 4-nitrocinnamamide as a crystalline solid (18.6 g). This product (18.6 g) wassuspended in ethanol (1 l) and hydrogenated using Pd-C catalyst (6.6 g)at 50 psi for 1 h. The resulting mixture was filtered and evaporated todryness, providing 4-aminophenyl propionamide (17.1 g).

Concentrated hydrochloric acid (4 ml) was added slowly, with cooling andstirring to 4-aminophenyl propionamide (0.80 g), maintaining thetemperature below 5° C. To this slurry was added a solution of sodiumnitrite (0.37 g) in water (2 ml), dropwise over 15 min, followed bystirring for a further 15 min. The turbid solution thus formed was addedportionwise to a cooled, stirred solution of stannous chloride (2.19 g)in conclusion. HCl (4 ml), and the resulting mixture was stirred for 1h. After filtering, the solution was reduced in volume until aninorganic precipitate formed. This was filtered off, and the filtratewas evaporated to dryness. The residual gum was crystallized from aceticacid to give crude 4-hydrazinophenyl propionamide hydrochloride (1.05g).

A mixture of the above product (1.05 g) and 4-phthalimido-cyclohexanone(1.18 g) in acetic acid (40 ml) was heated under reflux for 40 min. Thesolvent was removed in vacuo and the residue was partitioned betweenaqueous potassium carbonate solution and ethyl acetate. The organicphase was dried (MgSO₄) and evaporated to dryness, and the residue waschromatographed (SiO₂ ; CH₂ Cl₂ /MeOH) to give3-phthalimido-6-carboxamidoethyl-1,2,3,4-tetrahydrocarbazole (0.70 g).

This product (0.70 g) was dissolved in methanol (50 ml), treated withhydrazine hydrate (1.0 ml), and heated under reflux for 30 min. Themixture was evaporated to dryness then partitioned between ethyl acetateand aqueous potassium carbonate solution. The organic phase was dried(MgSO₄) and evaporated to dryness, and the residue was dissolved inethanol to dryness, and the residue was dissolved in ethanol and treatedwith oxalic acid (83 mg) in ethanol. A solid was formed, which wasrecrystallized from ethanol to give the title compound (110 mg), mp232°-5° C.

Pharmaceutical Formulations

EXAMPLE A

A tablet for oral administration is prepared by combining

    ______________________________________                                                               Mg/Tablet                                              ______________________________________                                        Compound of formula (I)                                                                              100                                                    lactose                153                                                    starch                 33                                                     crospovidone           12                                                     microcrystalline cellulose                                                                           30                                                     magnesium stearate     2                                                                             330    mg                                              ______________________________________                                    

into a 9 mm tablet.

EXAMPLE B

An injection for parenteral administration is prepared from thefollowing

    ______________________________________                                                              % w:w                                                   ______________________________________                                        Compound of formula (I)                                                                             0,50% (w:v)                                             1M citric acid        30% (v:v)                                               sodium hydroxide (qs) to pH 3.2                                               water for injection BP                                                                              to 100 ml                                               ______________________________________                                    

The compound of formula (I) is dissolved in the citric acid and the pHslowly adjusted to pH 3.2 with the sodium hydroxide solution. Thesolution is then made up to 100 ml with water, sterilised by filtrationand sealed into appropriately sized ampoules and vials.

We claim:
 1. A compound of the general formula (I): ##STR9## wherein: R¹is a group --(CH₂)_(n) CONR⁵ R⁶ ;n is zero; R⁵ and R⁶ each independentlyrepresent hydrogen, methyl, ethyl or propyl; and R² and R³ eachindependently represent hydrogen or C₁₋₆ alkyl provided both are nothydrogen;or a pharmaceutically acceptable salt thereof.
 2. A compound ofclaim 1 wherein R² and R³ each independently represent hydrogen, methylor ethyl.
 3. A compound of claim 2 wherein R⁵ and R⁶ each independentlyrepresent hydrogen or methyl.
 4. A compound of claim 1, which isselected from3-n-propylamino-6-carboxamido- 1,2,3,4-tetrahydrocarbazole;3-i-propylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole, or a saltthereof.
 5. A compound of claim 1, which is selectedfrom3-(N-(methyl)ethylamino)-6-carboxamido-1,2,3,4-tetrahydrocarbazole;3-dimethylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole;3-ethylamino-6-carboxamido- 1,2,3,4-tetrahydrocarbazole;or apharmaceutically acceptable salt thereof. 6.3-Benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole; or saltthereof.
 7. 3-Pyrrolidinyl-6-carboxamido-1,2,3,4-tetrahydrocarbazole, orsalt thereof.
 8. A pharmaceutical composition comprising a compound ofclaim 1 or a pharmaceutically acceptable salt thereof, and aphysiologically acceptable carrier.
 9. A pharmaceutical compositioncomprising a compound of claim 3 or a pharmaceutically acceptable saltthereof, and a physiologically acceptable carrier.
 10. A method oftreatment of a condition wherein a 5-HT₁ -like agonist is indicated,which comprises administering to a subject in need thereof an effectiveamount of a compound of claim
 1. 11. A method of claim 10 wherein in acompound of formula (I) R⁵ and R⁶ each independently represent hydrogenand methyl and R¹ and R² each represent hydrogen, methyl or ethylprovided R¹ and R² are not both hydrogen.